The limited self-renewal capacity of most human cell types that contributes to aging is recapitulated in vitro by primary fibroblasts that undergo replicative senescence. Stabilization of telomeric repeat arrays is sufficient to bypass this process and confer the potential for unlimited cellular division. This cellular immortality is also critical for tumorigenesis, an escalating health problem as the average age of the population increases. Telomerase activation is the common mechanism used by stem cells and tumors for maintenance of telomeric DNA. However, a subset of tumors and cell lines use a telomerase-independent mechanism, termed Alternative Lengthening of Telomeres (ALT), to sustain telomeric DNA. ALT provides a rescue pathway tumor cells might activate to overcome the deleterious effects of telomere attrition induced by inhibition of telomerase. Current evidence suggests that ALT depends on telomeric recombination. The tumor suppressor p53 negatively regulates recombination and telomere maintenance by ALT correlates with mutational inactivation of p53. Consistent with this, reintroduction of p53 into ALT cells results in growth suppression via a mechanism that does not require changes in gene expression but does require a direct interaction with the telomeric complex and intact suppression of recombination function. In addition, recent evidence indicates that, while ALT is also active in mice, telomerase and ALT are not functionally equivalent. These data suggest that although ALT may act as a substitute for telomerase with respect to telomere maintenance, its effects on tumor progression may be distinct.
alternative lengthening of telomeres